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Towards a comprehensive solution to cartilage repair: combining mechanotransduction with drug delivery
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Towards a comprehensive solution to cartilage repair: combining mechanotransduction with drug delivery

Shubhra Rastogi
Master of Science (M.S.), Drexel University
Jun 2020
DOI:
https://doi.org/10.17918/00000035
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Abstract

Three-dimensional imaging Polymeric drug delivery systems Macrophages Mechanotransduction, Cellular Tissue Engineering
An estimated 10% of the global population over the age of 60 have significant clinical problems that may be attributed to osteoarthritis. Current clinical solutions alleviate common symptoms; nothing on the market today addresses treatment of osteoarthritis itself. Regeneration of cartilage tissue lost in osteoarthritis is extremely challenging due to an innate lack of blood vessels, lymphatics and nerves. Tissue engineering may provide alternative solutions by developing biomimetic tissue substitutes. The goal of this project is to investigate how combination of biomechanical and biochemical properties can be used to create a pro-chondrogenic microenvironment, by means of controlled mechanotransduction and drug-delivery. To achieve such a goal, a novel technique is used to fabricate a fibrous, three-dimensional scaffold from natural polymer. Microfibers are generated by repeatedly stretching and folding gelatin sheathed in a sacrificial layer of PCL. Increasing the number of stretch-fold cycles reduces the fiber diameter while increasing the number of gelatin cores. After the PCL is dissolved, microfibers of three diameters are collected and UV-crosslinked into scaffolds. This provides scaffolds with microscopic pores that are either below or above than the typical size of cells, controlling of how cells sense and respond to mechanical environment, and subsequent signaling pathways that influence cartilage regeneration. IL-4 encapsulated PLGA microparticles were also synthesized, and embedded within the fibrous scaffold. Drug delivery from the final crosslinked product was measured over time to show continuous drug release for ~1 week. Modulation of phenotype after IL-4 stimulation was also explored. By combining mechanotransduction with drug delivery, this project aimed to investigate immunomodulatory properties of this scaffold to encourage macrophage polarization to the M2 phenotype. While M1 macrophages are known to promote inflammation and recruitment, M2 macrophages are known to release pro-chondrogenic, anti-inflammatory cytokines. Modulation of these properties may influence chondrogenic potential of cells at the injury site. Mechanotransduction of macrophages, in terms of attachment and activation, has been shown to be influenced by scaffold fiber diameter as well as pore size. Administration of IL-4 is known to promote the M2 phenotype both in-vitro and in-vivo. Both properties were combined here to approach the most pro-chondrogenic scaffold. Keywords: 3D Scaffold, Drug Delivery, Macrophage, Mechanotransduction, Microfiber Scaffold

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